Welcome to the VICC-CP Wiki

General Thoughts

There are five types of users in the VICC-CP:

Superuser
Standard user
Read only user
Anonymous user
Account manager

An anonymous user can not view or edit any variant information on VICC-CP. Anonymous users must ask an account manager to create an account for them. As the name implies, the read only user can only view information. He can neither insert variants nor classify them. The standard user is allwed to view and edit information on VICC-CP and the superuser has access to the admin dashboard which allows him to reannotate all variants at once.
The account manager is a special role which allows the user to create and modify user data. It is very easy to differentiate external links from internal ones:

The workflow

Insert variants

Variants can be inserted from the create variant page.
The VICC-CP allows to insert variants manually, from HGVS, VCF file or TSV. The TSV import will ignore any lines starting with '#'. And the format of the TSV is be chromosome "tabulator" genomic start "tabulator" genomic end "tabulator" reference sequence "tabulator" alternative sequence.
New variants are automatically added to the annotation queue and will be processed once a worker is ready to process it. The status of the annotation can be seen when navigation to the variant details page.

Browse variants

To find the variant you are looking for navigate to the search variants page. This page shows a paginated table of all variants. Note that the HGVS c. and HGVS p. columns are dependent on the transcript. Thus, these two columns show the HGVS strings of the preferred transcript (MANE -> longest coding -> longest non coding). If the variant is contained within more than one gene all of the HGVS strings from the preferred transcripts of all genes are shown. The "Your classification" shows your most recent user classification for this variant.
To filter the table of all variants click the -button to the top right. The search is explained in more detail here
It is also possible to add all variants which satisfy the current filtering criteria to a user defined list by clicking the "Add to list" button located at the bottom left. To create a new list go here.
Clicking on any of the rows will get you to its variant details page.

The variant details page

This page displays all annotations of a variant. The top headline shows the variant and its most recent HediVar consensus classification. There are six types of consensus classifications:

These are interpreted as follows:

-: no classification
1: benign
2: likely benign
3: uncertain
4: likely oncogenic
5: oncogenic

Right below the headline one can find status information about the variant. The first pill shows the status of the annotation. It could be queued, processing, done or erroneous. Next to the annotation status pill is the ClinVar submission status. This shows if the variant was already uploaded to ClinVar from HerediVar. When you click the -button the website presents options on what to do with the variant.
The main body of the page displays visualizations, classifications and annotations which are organized in multiple tabs. The tabs contain the following information:

Classification: VICC-CP consensus classification, VICC-CP user classifications, ClinVar classifications, BRCA exchange and ARUP BRCA classifications
Population & in-silico annotations: phylop-100way, cadd scaled, revel, spliceai, maxentscan, gnomAD, cancerhotspots, tp53db, VEST4, FATHMM-XF, CHASMplus
Gene annotations: NCG7.0 oncogenicity scores, GnomAD oe
OncoKB: biological function, clinical implication
Consequence: The variant consequences with associated HGVS strings and protein domains
Literature: Papers annotated by VEP, TP53db and litvar2
IGV: The IGV genome browser. The first track shows the variant itself. The second track shows all classified variants (click on them to find a link to the variant details page). The third track shows the ensembl transcripts. Red transcripts are MANE select or MANE plus clinical transcripts, orange ones are ensembl canonical and dark blue ones are gencode basic transcripts. Other transcripts which do not satisfy the aforementioned criteria are not shown.

Remember that the annotations are not shown if the variant is not known to the respective database.

User classification

To classify a variant click the -button on the variant details page and select "Classify". On the classify variant page you can first select if you want to insert a user classification or a consensus classification. However, only superusers can insert consensus classifications. Next, select the cancertype you wish to classify this variant for. You may choose to classify the variant for no specific cancertype. In this case select "Pan cancer (NULL)". The presented cancertypes (except for "Pan cancer") originate from the oncotree ontology for cancertypes (visit the official website of oncotree here). The website will automatically select "Pan cancer" if you did not classify the variant yet. If you already have a classification for this variant the website will try to choose the best cancertype.
To select a criterion follow these steps:

Select the criterion
Insert evidence (eg. use the information provided in the "Important information" section)
Optional: insert literature (you may insert PMIDs, DOIs or choose from the provided list of papers)
Select the criterion state

The following criterion states are possible:

unchecked: we do not have enough evidence to say anything about this criterion -> not assessed / unknown evidence
selected: evidence suggests this criterion is true -> assessed / true evidence
unselected: evidence suggests this criterion should not be selected -> we KNOW that this criterion is not selected because of evidence -> Use this for documentation purposes

Evidence should always be provided for selected and unselected states!
The classification preview to the right will update automatically based on the selected criteria.
Note that each user can only have one user classification per variant and scheme, but they can be edited anytime.

Consensus classification

To classify a variant click the -button on the variant details page and select "Classify". On the classify variant page you can first select if you want to insert a user classification or a consensus classification. Consensus classifications work very similar to user classifications. The only difference is that the number of users who selected a criterion is displayed next to the criterion like so:

The selected criterion, "OVS1" was chosen by two VICC-CP users to be important for this variant. The actual user input is shown in the "User selections" table. When you click the copy symbol it is possible to quickly copy the data of that user. Now you only have to select the criterion by clicking the checkbox next to the name of the criterion.

Automatic classification

The classify variant page also provides help to choose some criteria. Simply use the "preselect criteria" button. Options, like the transcript of interest and the computational evidence scores to consider for OP1 and SBP1 can be adjusted. The "choose best transcript automatically" option will select the MANE transcript and if that gene does not have a MANE transcript it will choose the longest coding. If there are no coding transcripts it will choose the longest non-coding transcript. It is very important to check every preselected criterion and accept or reject the decision of the algorithm. Also, OS3, OM1, OM4 and OP2 can not be selected automatically. Details about the automatic classification algorithm:

OVS1 (null mutation):
is ncg tsg AND mutation class: stop gained, frameshift, splice or startcodon
OS1 (known oncogenic variant):
cmc mutation significance 1-3 OR variant that causes the same amino acid change and is classified as (likely) pathogenic in ClinVar
OS3 (strong cancerhotspot):
Cancerhotspot total (AC) >= 50 AND Cancerhotspot alt (number of occurances) >= 10
OM2 (protein length change):
is ncg oncogene or tsg AND variant class: inframe insertion/deletion
OM3 (intermediate cancer hotspot):
Cancerhotspot total less than 50 AND Cancerhotspot alt >= 10
OM4 (alternate missense variant):
Another missense variant in the same codon with Grantham distance >= Grantham distance of observed amino acid change and classified as (likely) pathogenic in ClinVar
OP1 (computational evidence):
Depending on which scores you choose:
Revel > 0.5 AND CADD > 20 AND FATHMM-XF < -1.5 AND CHASM < 0.05 (p-value) AND VEST4 < 0.05 (p-value)
OP2 (genetic etiology):
not preselected
OP3 (weak cancer hotspot):
0 < Cancerhotspot alt count < 10
OP4 (absent from controls):
gnomAD AF < 0.001
SBVS1 (high minor AF):
gnomad > 0.05
SBS1 (intermediate minor AF):
0.05 <= gnomad > 0.01
SBS2 (appears in functional studies):
clinvar class 1 or 2 (interpretation summary)
SBP1 (computational evidence):
Depending on which scores you choose:
Revel <= 0.5 AND CADD <= 20 AND FATHMM-XF >= -1.5 AND CHASM >= 0.05 (p-value) AND VEST4 >= 0.05 (p-value)
SBP2 (synonymes and high oe scores):
mutation class synonymous AND oe_syn > 0.1

User variant lists

Each registered user can add new variant lists here. Click the "+" button:

Enter a name for the list and select if it is readable / editable by all users. If a list is only readable everyone can see the list, but they can not add or remove variants from it. This is however possible when the list is also editable.
There are two ways to insert variants to the newly created variant list. The first one is to navigate to the browse variants page, search for variants and click the "Add all to list" button at the bottom left of this page. This will insert all variants satisfying the criteria of the current search.
The second possibility to add variants to a list on a one-by-one basis is to navigate to the variant details page, click the -button and select "Add to list".
All variants collected in these ways are displayed when clicked on the name of the variant at the user lists page. The table of variants behaves exactly the same as the one shown on the browse variants page. It can be filtered and when a row is clicked it takes you to the variant details page.
It is also possible to export all variants in one of the lists to vcf by clicking the "Export to VCF" button on the bottom of the page.
If you want to change the properties or delete a list that was created by you. Just click the little pencil button next to the list name. Beware that private lists can not be seen by other users.

Download data

Registered users are able to download a vcf file for one variant through the respective variant details page by clicking the gear button and selecting "Export to VCF". This file will contain all information that are available for this variant. Including all annotations and classifications.

If a registered user wants to download more than one variant in a single file they have to collect relevant variants in a user defined list (see previous section on how to create one). Then, simply click the "Export list to VCF" button at the bottom right of the list details page.

In rare cases ClinVar submissions are missing although there is a ClinVar summary available. In such cases the clinvar_submissions info in the downloaded vcf file will be set to None. This is usually because of erroneous data hosted by ClinVar and is often fixed by updating ClinVar.

In any case, downloaded VCF files are encoded using the url encoding (Wikipedia). Excluding whitespace, which is replaced with underscores "_". This ensures that the file is machine readable and consistent when special characters that are also used as delimiters are used within the actual information. It is fast forward to revert the encoding once relevant information was read from the file. Many programming languages support url decoding out of the box.

The downloaded VCF files from HerediVar always adhere to this delimiter order (please report if this is not the case):

;
&
|
$
+

User management

Create a new user

Only users with the "account_manager" role are allowed to create new users. There is no possibility to self-register in HerediVar. An account manager can go here to create a new user account. Simply fill out the form which is presented to you. Keep in mind that the username must be unique and can not be changed later. The mail address must be unique as well.
Upon submission Heredivar will automatically notify the user that about the newly created account using the provided e-mail. The new user will recieve two mails: one with the username specified and one with an automatically generated initial password.

Change roles & disable users

An account manager can edit existing users by visiting this page. Simply select a user from the list to edit its information. It is possible to disable users or change their roles from this page.
Keep in mind that changeing the e-mail will require the user to verify the mail upon next login.

Change password

Every user can change their own password by visiting this page. This will redirect to the keycloak account management console. First click the Update-button:

Then, you are probably asked to re-authenticate using your old password. After that you can insert a new password.